NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.

Nonalcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver, and it is associated with liver-related complications and adverse systemic diseases. NAFLD has become the most prevalent liver disease; however, effective therapeutic agents for NAFLD are still lacking. We combined clinical data with proteomics and metabolomics data, and found that the mitochondrial nucleoside diphosphate kinase NME4 plays a central role in mitochondrial lipid metabolism. Nme4 is markedly upregulated in mice fed with high-fat diet, and its expression is positively correlated with the level of steatosis. Hepatic deletion of Nme4 suppresses the progression of hepatic steatosis. Further studies demonstrated that NME4 interacts with several key enzymes in coenzyme A (CoA) metabolism and increases the level of acetyl-CoA and malonyl-CoA, which are the major lipid components of the liver in NAFLD. Increased level of acetyl-CoA and malonyl-CoA  lead to increased triglyceride levels and lipid accumulation in the liver. Taken together, these findings reveal that NME4 is a critical regulator of NAFLD progression and a potential therapeutic target for NAFLD.

Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.

AIMS/HYPOTHESIS: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD. METHODS: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions. RESULTS: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes. CONCLUSIONS/INTERPRETATION: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

Advances and challenges in measuring hepatic glucose uptake with FDG PET: implications for diabetes research.

The liver plays a crucial role in the control of glucose homeostasis and is therefore of great interest in the investigation of the development of type 2 diabetes. Hepatic glucose uptake (HGU) can be measured through positron emission tomography (PET) imaging with the tracer [18F]-2-fluoro-2-deoxy-D-glucose (FDG). HGU is dependent on many variables (e.g. plasma glucose, insulin and glucagon concentrations), and the metabolic state for HGU assessment should be chosen with care and coherence with the study question. In addition, as HGU is influenced by many factors, protocols and measurement conditions need to be standardised for reproducible results. This review provides insights into the protocols that are available for the measurement of HGU by FDG PET and discusses the current state of knowledge of HGU and its impairment in type 2 diabetes. Overall, a scanning modality that allows for the measurement of detailed kinetic information and influx rates (dynamic imaging) may be preferable to static imaging. The combination of FDG PET and insulin stimulation is crucial to measure tissue-specific insulin sensitivity. While the hyperinsulinaemic-euglycaemic clamp allows for standardised measurements under controlled blood glucose levels, some research questions might require a more physiological approach, such as oral glucose loading, with both advantages and complexities relating to fluctuations in blood glucose and insulin levels. The available approaches to address HGU hold great potential but await more systematic exploitation to improve our understanding of the mechanisms underlying metabolic diseases. Current findings from the investigation of HGU by FDG PET highlight the complex interplay between insulin resistance, hepatic glucose metabolism, NEFA levels and intrahepatic lipid accumulation in type 2 diabetes and obesity. Further research is needed to fully understand the underlying mechanisms and potential therapeutic targets for improving HGU in these conditions.

Effects of physical activity on the levels of remnant cholesterol: A population-based study.

Physical activity (PA) has the potential to bring about favourable changes in plasma lipid profile. However, the relationship between PA and remnant cholesterol (RC) remains unclear. We aimed to study the link between PA and RC using the database of the 2007-2020 National Health and Nutrition Examination Survey (NHANES). PA was categorized based on Physical Activity Guidelines for Americans. A multivariate linear regression model was used to determine the correlations between PA and RC. The study involved a total of 18,396 participants and revealed that individuals whose PA met the guidelines by engaging in moderate-intensity PA at least 150 min per week had lower body mass index and showed decreased levels of triglyceride, TC, and haemoglobin A1c compared to those who were physically inactive, exercising <150 min per week. Participants whose intensity of PA meets PA guidelines had a lower level of RC than those who did not met PA guidelines (ß = -1.3, 95% confidence interval [CI]: -1.9 to -0.7, p < 0.001), even after adjusting for confounders. During subgroup analysis, we observed that race (pinteraction = 0.0089) emerged as a significant factor of interaction.

Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1R345W, a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD.

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.

Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.

The anti-atherosclerotic effect of Paeonol against the lipid accumulation in macrophage-derived foam cells by inhibiting ferroptosis via the SIRT1/NRF2/GPX4 signaling pathway.

Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.

Sesamin alleviates lipid accumulation induced by oleic acid via PINK1/Parkin-mediated mitophagy in HepG2 cells.

Sesamin, a special compound present in sesame and sesame oil, has been reported a role in regulating lipid metabolism, while the underlying mechanisms remain unclear. Autophagy has been reported associated with lipid metabolism and regarded as a key modulator in liver steatosis. The present work aimed to investigate whether sesamin could exert its protective effects against lipid accumulation via modulating autophagy in HepG2 cells stimulated with oleic acid (OA). Cell viability was evaluated using the CCK-8 method, and triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein, cholesterol (LDL-C), alanine aminotransferase (ALT), along with aspartate aminotransferase (AST) were assessed by oil red O staining, transmission electron microscopy (TEM), and biochemical kits to investigate the lipid-lowering effects of sesamin. Differentially expressed genes were screened by RNA sequencing and validated using real-time quantitative PCR and Western blot. Autophagy and mitophagy related molecules were analyzed employing TEM, Western blot, and immunofluorescence. The data shows that in HepG2 cells stimulated by OA, sesamin reduces levels of TG, TC, LDL-C, ALT, and AST while elevating HDL-C, alleviates the lipid accumulation and improves fatty acid metabolism through modulating the levels of fat metabolism related genes including PCSK9, FABP1, CD36, and SOX4. Sesamin restores the suppressed autophagy in HepG2 cells caused by OA, which could be blocked by autophagy inhibitors. This indicates that sesamin improves fatty acid metabolism by enhancing autophagy levels, thereby mitigating the intracellular lipid accumulation. Furthermore, sesamin significantly enhances the mitophagy and improves mitochondrial homeostasis via activating the PINK/Parkin pathway. These data suggest that sesamin alleviates the excessive lipid accumulation in HepG2 caused by OA by restoring the impaired mitophagy via the PINK1/Parkin pathway, probably playing a preventive or therapeutic role in hepatic steatosis.

Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity.

BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.

A WRI1-dependent module is essential for the accumulation of auxin and lipid in somatic embryogenesis of Arabidopsis thaliana.

The potential for totipotency exists in all plant cells; however, the underlying mechanisms remain largely unknown. Earlier findings have revealed that the overexpression of LEAFY COTYLEDON 2 (LEC2) can directly trigger the formation of somatic embryos on the cotyledons of Arabidopsis. Furthermore, cotyledon cells that overexpress LEC2 accumulate significant lipid reserves typically found in seeds. The precise mechanisms and functions governing lipid accumulation in this process remain unexplored. In this study, we demonstrate that WRINKLED1 (WRI1), the key regulator of lipid biosynthesis, is essential for somatic embryo formation, suggesting that WRI1-mediated lipid biosynthesis plays a crucial role in the transition from vegetative to embryonic development. Our findings indicate a direct interaction between WRI1 and LEC2, which enhances the enrichment of LEC2 at downstream target genes and stimulates their induction. Besides, our data suggest that WRI1 forms a complex with LEC1, LEC2, and FUSCA3 (FUS3) to facilitate the accumulation of auxin and lipid for the somatic embryo induction, through strengthening the activation of YUCCA4 (YUC4) and OLEOSIN3 (OLE3) genes. Our results uncover a regulatory module controlled by WRI1, crucial for somatic embryogenesis. These findings provide valuable insights into our understanding of plant cell totipotency.

Melatonin ameliorates simulated-microgravity-induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes.

The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.

Traumatic acid inhibits ACSL4 associated lipid accumulation in adipocytes to attenuate high-fat diet-induced obesity.

Obesity is a major health concern that lacks effective intervention strategies. Traumatic acid (TA) is a potent wound-healing agent in plants, considered an antioxidant food ingredient. This study demonstrated that TA treatment significantly reduced lipid accumulation in human adipocytes and prevented high-fat diet induced obesity in zebrafish. Transcriptome sequencing revealed TA-activated fatty acid (FA) degradation and FA metabolism signaling pathways. Moreover, western blotting and quantitative polymerase chain reaction showed that TA inhibited the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Overexpression of ACSL4 resulted in the reversal of TA beneficiary effects, indicating that the attenuated lipid accumulation of TA was regulated by ACSL4 expression. Limited proteolysis-mass spectrometry and microscale thermophoresis were then used to confirm hexokinase 2 (HK2) as a direct molecular target of TA. Thus, we demonstrated the molecular basis of TA in regulating lipid accumulation and gave the first evidence that TA may function through the HK2-ACSL4 axis.

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.

The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG-mediated pull-down capture followed by mass spectrometry assay showed that p160 Myb-binding protein (P160 MBP; Mybbp1 a $$ a $$ ), the critical transcriptional repressor of PGC-1α, was bound to lamin A/C. Increased Mybbp1 a $$ a $$ levels in tissues and greater Mybbp1 a $$ a $$ -lamin A/C binding in nuclear inhibit PGC-1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC-1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.

Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction.

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.

CircZNF609 sponges miR-135b to up-regulate SEMA3A expression to alleviate ox-LDL-induced atherosclerosis.

The initiation and progression of atherosclerotic plaque caused by abnormal lipid metabolism is one of the main causes of atherosclerosis (AS). Lipid droplet accumulation has become a novel research pointcut for AS treatment in recent years. In AS patients, miR-135b level was up-regulated relative to the normal cases, which showed negative correlations with the levels of Semaphorin 3A (SEMA3A) and circZNF609, separately. The U937-derived macrophages were cultured with ox-LDL to establish AS models in vitro. After that, the lipid accumulation, inflammation, mitochondrial dysfunction and cell death were evaluated by ORO, ELISA, RT-qPCR, western blot, JC-1 and FCM assays respectively. Transfection of the circZNF609 expression vector notably declined lipid accumulation, attenuated inflammation, reduced mitochondrial dysfunction and inhibited cell death in ox-LDL-stimulated cells. The direct binding of miR-135b to circZNF609 in vitro was confirmed using RIP assay, and SEMA3A expression was up-regulated by circZNF609 overexpression. After manipulating the endogenous expressions of circZNF609, miR-135b and SEMA3A, the above damages in ox-LDL-stimulated cells were rescued by inhibition of miR-135b expression and overexpression of circZNF609 or SEMA3A. Besides, the AS mice model was built to demonstrate the excessive lipid accumulation, increasing inflammation and cell death in AS pathogenesis according to the results of HE staining, ELISA and IHC assays, while these damages were reversed after overexpression of circZNF609 or SEMA3A. In AS models, overexpressed circZNF609 prevents the AS progression through depleting miR-135b expression and subsequent up-regulation of SEMA3A expression to overwhelm lipid accumulation, mitochondrial dysfunction and cell death.

Nitrogen starvation causes lipid remodeling in Rhodotorula toruloides.

BACKGROUND: The oleaginous yeast Rhodotorula toruloides is a promising chassis organism for the biomanufacturing of value-added bioproducts. It can accumulate lipids at a high fraction of biomass. However, metabolic engineering efforts in this organism have progressed at a slower pace than those in more extensively studied yeasts. Few studies have investigated the lipid accumulation phenotype exhibited by R. toruloides under nitrogen limitation conditions. Consequently, there have been only a few studies exploiting the lipid metabolism for higher product titers. RESULTS: We performed a multi-omic investigation of the lipid accumulation phenotype under nitrogen limitation. Specifically, we performed comparative transcriptomic and lipidomic analysis of the oleaginous yeast under nitrogen-sufficient and nitrogen deficient conditions. Clustering analysis of transcriptomic data was used to identify the growth phase where nitrogen-deficient cultures diverged from the baseline conditions. Independently, lipidomic data was used to identify that lipid fractions shifted from mostly phospholipids to mostly storage lipids under the nitrogen-deficient phenotype. Through an integrative lens of transcriptomic and lipidomic analysis, we discovered that R. toruloides undergoes lipid remodeling during nitrogen limitation, wherein the pool of phospholipids gets remodeled to mostly storage lipids. We identify specific mRNAs and pathways that are strongly correlated with an increase in lipid levels, thus identifying putative targets for engineering greater lipid accumulation in R. toruloides. One surprising pathway identified was related to inositol phosphate metabolism, suggesting further inquiry into its role in lipid accumulation. CONCLUSIONS: Integrative analysis identified the specific biosynthetic pathways that are differentially regulated during lipid remodeling. This insight into the mechanisms of lipid accumulation can lead to the success of future metabolic engineering strategies for overproduction of oleochemicals.

Association between lipid accumulation products and osteoarthritis among adults in the United States: A cross-sectional study, NHANES 2017-2020.

OBJECTIVE: Using cross-sectional data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) for American, the aim of this research is to investigate the potential association between Lipid Accumulation Products (LAP) and the risk of osteoarthritis (OA). METHODS: Data from the NHANES (2017-2020) were downloaded and further analyzed. The participants between 20 and 80 years reported having OA, and other relevant variables and information on LAP were included. The linear and non-linear associations between LAP and OA were evaluated using multivariable logistic regression analysis and smoothed curve fitting methods. A two-part linear regression model was also used to estimate threshold effects. RESULTS: The increased risk of OA was shown to have a nonlinear relationship with higher LAP, showing a solid threshold impact with a saturation value of 120.00 cm × mmol/L, according to our data. The two variables showed a positive relationship to the left of the saturation point but no significant association to the right, pointing to a complicated nonlinear relationship between OA prevalence and LAP. CONCLUSIONS: Our findings revealed that LAP was an independent risk factor for OA when it was <120.00 cm × mmol/L. The LAP index may serve as a valuable method for predicting and diagnosed OA. To validate our results, further large-scale prospective research are required.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.